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EBioMedicine Dec 2021Biliary Atresia is a devastating pediatric cholangiopathy affecting the bile ducts of the liver. In this review, we describe recent progress in the understanding of... (Review)
Review
Biliary Atresia is a devastating pediatric cholangiopathy affecting the bile ducts of the liver. In this review, we describe recent progress in the understanding of liver development with a focus on cholangiocyte differentiation and how use of technical platforms, including rodent, zebrafish and organoid models, advances our understanding of Biliary Atresia. This is followed by a description of potential pathomechanisms, such as autoimmune responses, inflammation, disturbed apical-basal cell polarity, primary cilia dysfunction as well as beta-amyloid accumulation. Finally, we describe current and emerging diagnostic opportunities and recent translation breakthroughs for Biliary Atresia in the area of emerging therapy development, including immunomodulation and organoid-based systems for liver and bile duct repair.
Topics: Animals; Bile Ducts; Biliary Atresia; Cell Differentiation; Disease Models, Animal; Epithelial Cells; Humans; Organoids
PubMed: 34781099
DOI: 10.1016/j.ebiom.2021.103689 -
Annals of Hepatology 2022Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it... (Review)
Review
Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it is sub-classified as intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), the latter comprising both perihilar cholangiocarcinoma (pCCA or Klatskin tumor), and distal cholangiocarcinoma (dCCA). The global incidence of CCA has increased worldwide in recent decades. Chronic inflammation of biliary epithelium and bile stasis represent the main risk factors shared by all CCA sub-types. When feasible, liver resection is the treatment of choice for CCA, followed by systemic chemotherapy with capecitabine. Liver transplants represent a treatment option in patients with very early iCCA, in referral centers only. CCA diagnosis is often performed at an advanced stage when CCA is unresectable. In this setting, systemic chemotherapy with gemcitabine and cisplatin represents the first treatment option, but the prognosis remains poor. In order to ameliorate patients' survival, new drugs have been studied in the last few years. Target therapies are directed against different molecules, which are altered in CCA cells. These therapies have been studied as second-line therapy, alone or in combination with chemotherapy. In the same setting, the immune checkpoints inhibitors targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), have been proposed, as well as cancer vaccines and adoptive cell therapy (ACT). These experimental treatments showed promising results and have been proposed as second- or third-line treatment, alone or in combination with chemotherapy or target therapies.
Topics: Bile Duct Neoplasms; Bile Ducts, Extrahepatic; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Humans; Klatskin Tumor
PubMed: 35809836
DOI: 10.1016/j.aohep.2022.100737 -
ESMO Open Feb 2022Management of biliary tract cancers (BTCs) is rapidly evolving. Curative management relies on surgical resection followed by adjuvant capecitabine for cholangiocarcinoma... (Review)
Review
Management of biliary tract cancers (BTCs) is rapidly evolving. Curative management relies on surgical resection followed by adjuvant capecitabine for cholangiocarcinoma and gallbladder cancers. Unfortunately relapse rate remains high, and better adjuvant strategies are urgently required. A majority of patients are diagnosed with advanced disease, when chemotherapy with cisplatin and gemcitabine followed by second-line 5-FU and oxaliplatin /irinotecan is the cornerstone of treatment for most patients in the absence of targetable alterations. Targeted therapies, including therapies for tumours with fibroblast growth factor receptor-2 (FGFR-2) fusions, isocitrate dehydrogenase-1 (IDH-1) mutations, B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E mutations, neurotrophic tyrosine receptor kinase (NTRK) fusions, Human epidermal growth factor-2 (HER-2) amplifications, and/or microsatellite instability are rapidly changing the treatment paradigm for many patients with advanced BTC, especially for patients with intrahepatic cholangiocarcinoma. Because of this, molecular profiling should be considered early on patients pathway to allow adequate planning of therapy. Ongoing research is likely to clarify the role of immunotherapy, liver-directed therapy, and liver transplant for BTCs in the future.
Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biliary Tract Neoplasms; Cholangiocarcinoma; Humans; Neoplasm Recurrence, Local
PubMed: 35032765
DOI: 10.1016/j.esmoop.2021.100378 -
Methods in Molecular Biology (Clifton,... 2022Cholangiopathies affect the biliary tree via various pathophysiological mechanisms. Research on biliary physiology and pathology, however, is hampered by a lack of...
Cholangiopathies affect the biliary tree via various pathophysiological mechanisms. Research on biliary physiology and pathology, however, is hampered by a lack of physiologically relevant in vitro models. Conventional models, such as two-dimensional (2D) monolayers and organoids, fail to replicate the structural organization of the bile duct, and both the size of the duct and position of cells are difficult to manipulate in a controllable way. Here, we describe a bile duct-on-a-chip (BDOC) that phenocopies the open-ended tubular architecture of the bile duct in three dimensions which, when seeded with either a cholangiocyte cell line or primary cells, demonstrates barrier function similar to bile ducts in vivo. This device represents an in vitro platform to study the pathophysiology of the bile duct using cholangiocytes from a variety of sources.
Topics: Bile Ducts; Epithelial Cells; Lab-On-A-Chip Devices; Organoids
PubMed: 34520006
DOI: 10.1007/978-1-0716-1693-2_4 -
Cell Stem Cell May 2022Human cholangiocyte organoids show great promise for regenerative therapies and in vitro modeling of bile duct development and diseases. However, the cystic organoids...
Human cholangiocyte organoids show great promise for regenerative therapies and in vitro modeling of bile duct development and diseases. However, the cystic organoids lack the branching morphology of intrahepatic bile ducts (IHBDs). Here, we report establishing human branching cholangiocyte organoid (BRCO) cultures. BRCOs self-organize into complex tubular structures resembling the IHBD architecture. Single-cell transcriptomics and functional analysis showed high similarity to primary cholangiocytes, and importantly, the branching growth mimics aspects of tubular development and is dependent on JAG1/NOTCH2 signaling. When applied to cholangiocarcinoma tumor organoids, the morphology changes to an in vitro morphology like primary tumors. Moreover, these branching cholangiocarcinoma organoids (BRCCAOs) better match the transcriptomic profile of primary tumors and showed increased chemoresistance to gemcitabine and cisplatin. In conclusion, BRCOs recapitulate a complex process of branching morphogenesis in vitro. This provides an improved model to study tubular formation, bile duct functionality, and associated biliary diseases.
Topics: Bile Ducts; Cholangiocarcinoma; Epithelial Cells; Humans; Organoids; Transcriptome
PubMed: 35523140
DOI: 10.1016/j.stem.2022.04.011 -
Surgical Endoscopy Jul 2020Bile duct injury (BDI) is the most common serious complication of laparoscopic cholecystectomy. To address this problem, a multi-society consensus conference was held to...
BACKGROUND
Bile duct injury (BDI) is the most common serious complication of laparoscopic cholecystectomy. To address this problem, a multi-society consensus conference was held to develop evidenced-based recommendations for safe cholecystectomy and prevention of BDI.
METHODS
Literature reviews were conducted for 18 key questions across six broad topics around cholecystectomy directed by a steering group and subject experts from five surgical societies (SAGES, AHPBA IHPBA, SSAT, and EAES). Evidence-based recommendations were formulated using the GRADE methodology. When evidence-based recommendations could not be made, expert opinion was documented. A number of recommendations for future research were also documented. Recommendations were presented at a consensus meeting in October 2018 and were voted on by an international panel of 25 experts with greater than 80% agreement considered consensus.
RESULTS
Consensus was reached on 17 of 18 questions by the Guideline Development Group (GDG) and expert panel with high concordance from audience participation. Most recommendations were conditional due to low certainty of evidence. Strong recommendations were made for (1) use of intraoperative biliary imaging for uncertainty of anatomy or suspicion of biliary injury; and (2) referral of patients with confirmed or suspected BDI to an experienced surgeon/multispecialty hepatobiliary team.
CONCLUSION
These consensus recommendations should provide guidance to surgeons, training programs, hospitals, and professional societies for strategies that have the potential to reduce BDIs and positively impact patient outcomes. Development of clinical and educational research initiatives based on these recommendations may drive further improvement in the quality of surgical care for patients undergoing cholecystectomy.
Topics: Bile Ducts; Cholecystectomy, Laparoscopic; Humans; Intraoperative Complications; Surgeons
PubMed: 32399938
DOI: 10.1007/s00464-020-07568-7 -
Digestive Surgery 2020Bile duct injury (BDI) is a devastating complication following cholecystectomy. After initial management of BDI, patients stay at risk for late complications including...
BACKGROUND
Bile duct injury (BDI) is a devastating complication following cholecystectomy. After initial management of BDI, patients stay at risk for late complications including anastomotic strictures, recurrent cholangitis, and secondary biliary cirrhosis.
METHODS
We provide a comprehensive overview of current literature on the long-term outcome of BDI. Considering the availability of only limited data regarding treatment of anastomotic strictures in literature, we also retrospectively analyzed patients with anastomotic strictures following a hepaticojejunostomy (HJ) from a prospectively maintained database of 836 BDI patients.
RESULTS
Although clinical outcomes of endoscopic, radiologic, and surgical treatment of BDI are good with success rates of around 90%, quality of life (QoL) may be impaired even after "clinically successful" treatment. Following surgical treatment, the incidence of anastomotic strictures varies from 5 to 69%, with most studies reporting incidences around 10-20%. The median time to stricture formation varies between 11 and 30 months. Long-term BDI-related mortality varies between 1.8 and 4.6%. Of 91 patients treated in our center for anastomotic strictures after HJ, 81 (89%) were treated by percutaneous balloon dilatation, with a long-term success rate of 77%. Twenty-four patients primarily or secondarily underwent surgical revision, with recurrent strictures occurring in 21%.
CONCLUSIONS
The long-term impact of BDI is considerable, both in terms of clinical outcomes and QoL. Treatment should be performed in tertiary expert centers to optimize outcomes. Patients require a long-term follow-up to detect anastomotic strictures. Strictures should initially be managed by percutaneous dilatation, with surgical revision as a next step in treatment.
Topics: Anastomosis, Roux-en-Y; Bile Ducts; Cholangitis; Cholecystectomy; Constriction, Pathologic; Dilatation; Humans; Iatrogenic Disease; Jejunum; Liver Cirrhosis, Biliary; Prognosis; Quality of Life; Recurrence; Reoperation; Retrospective Studies
PubMed: 30654363
DOI: 10.1159/000496432 -
Journal of Hepatology Dec 2022Cholangiocarcinomas are cancers arising from bile ducts, either found within the liver (intrahepatic) or outside the liver (extrahepatic). In Western countries, deaths... (Review)
Review
Cholangiocarcinomas are cancers arising from bile ducts, either found within the liver (intrahepatic) or outside the liver (extrahepatic). In Western countries, deaths due to intrahepatic cancers are rising at a higher rate than deaths due to extrahepatic cancers. This may be due to rising cases of liver disease and misclassification of the different cancer types.
Topics: Humans; Cholangiocarcinoma; Bile Ducts; Liver; Bile Duct Neoplasms; Bile Ducts, Intrahepatic
PubMed: 35977611
DOI: 10.1016/j.jhep.2022.07.022 -
Science (New York, N.Y.) Feb 2021Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the...
Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the context of cholangiopathies, which represent a key reason for liver transplantation. Using single-cell RNA sequencing, we show that primary human cholangiocytes display transcriptional diversity that is lost in organoid culture. However, cholangiocyte organoids remain plastic and resume their in vivo signatures when transplanted back in the biliary tree. We then utilize a model of cell engraftment in human livers undergoing ex vivo normothermic perfusion to demonstrate that this property allows extrahepatic organoids to repair human intrahepatic ducts after transplantation. Our results provide proof of principle that cholangiocyte organoids can be used to repair human biliary epithelium.
Topics: Animals; Bile; Bile Duct Diseases; Bile Ducts; Bile Ducts, Intrahepatic; Cell- and Tissue-Based Therapy; Common Bile Duct; Epithelial Cells; Gallbladder; Gene Expression Regulation; Humans; Liver; Liver Transplantation; Mesenchymal Stem Cell Transplantation; Mice; Organoids; RNA-Seq; Tissue and Organ Procurement; Transcriptome
PubMed: 33602855
DOI: 10.1126/science.aaz6964 -
The British Journal of Radiology Sep 2021Cholangitis refers to inflammation of the bile ducts with or without accompanying infection. When intermittent or persistent inflammation lasts 6 months or more, the... (Review)
Review
Cholangitis refers to inflammation of the bile ducts with or without accompanying infection. When intermittent or persistent inflammation lasts 6 months or more, the condition is classified as chronic cholangitis. Otherwise, it is considered an acute cholangitis. Cholangitis can also be classified according to the inciting agent, complete mechanical obstruction, which is the leading cause of acute cholangitis, longstanding partial mechanical blockage, or immune-mediated bile duct damage that results in chronic cholangitis.The work-up for cholangitis is based upon medical history, clinical presentation, and initial laboratory tests. Whereas ultrasound is the first-line imaging modality used to identify bile duct dilatation in patients with colicky abdominal pain, cross-sectional imaging is preferable when symptoms cannot be primarily localised to the hepatobiliary system. CT is very useful in oncologic, trauma, or postoperative patients. Otherwise, magnetic resonance cholangiopancreatography is the method of choice to diagnose acute and chronic biliary disorders, providing an excellent anatomic overview and, if gadoxetic acid is injected, simultaneously delivering morphological and functional information about the hepatobiliary system. If brush cytology, biopsy, assessment of the prepapillary common bile duct, stricture dilatation, or stenting is necessary, then endoscopic ultrasound and/or retrograde cholangiography are performed. Finally, when the pathologic duct is inaccessible from the duodenum or stomach, percutaneous transhepatic cholangiography is an option. The pace of the work-up depends upon the severity of cholestasis on presentation. Whereas sepsis, hypotension, and/or Charcot's triad warrant immediate investigation and management, chronic cholestasis can be electively evaluated.This overview article will cover the common cholangitides, emphasising our clinical experience with the chronic cholestatic liver diseases.
Topics: Bile Ducts; Cholangitis; Diagnostic Imaging; Humans
PubMed: 34233488
DOI: 10.1259/bjr.20210417